OHMR SOP Template - Home | Queensland Health · Web viewThis Clinical Investigator’s Brochure (CIB) was subject to critical review and has been approved by the following persons:

CONFIDENTIALCONFIDENTIAL

SOP 4 - Protocol and Investigational Brochure Content, Design, Amendments & ComplianceAppendix 2

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CLINICAL INVESTIGATOR’S BROCHURE CLINICAL INVESTIGATOR’S BROCHURE Investigational product:

Research name/number:

INN name:

Indication:

Sponsor

Telephone:

Fax:

Email:

Edition:

Release Date:

This document supersedes Edition number: X.0 dated:

CONFIDENTIALITY STATEMENT

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SPONSOR STATEMENT

This Clinical Investigator’s Brochure (CIB) was subject to critical review and has been approved by the following persons:

_________________________ ____________________

Signature Date

Name:

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Company

_________________________ ____________________

Signature Date

Name

Add position (Scientific)

Company

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Investigator’s Brochure CONFIDENTIALCONFIDENTIAL

Investigational Product

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TABLE OF CONTENTS

1. Summary......................................................................................................................................91.1. Background..........................................................................................................................91.2. Overview of investigational product....................................................................................91.3. Chemistry, Manufacturing and Controls..............................................................................91.4. Nonclinical Studies...............................................................................................................9

1.4.1. Pharmacology...............................................................................................................91.4.2. Pharmacokinetics..........................................................................................................91.4.3. Toxicology....................................................................................................................9

1.5. Clinical Experience..............................................................................................................91.6. Development plan.................................................................................................................9

2. Introduction................................................................................................................................102.1. Overview of targeted disease and indication......................................................................102.2. Investigational product.......................................................................................................102.3. Rationale for clinical development.....................................................................................102.4. Dose justification................................................................................................................10

3. Physical, Chemical and Pharmaceutical Properties AND Formulation.....................................113.1. Drug substance...................................................................................................................11

3.1.1. Manufacture................................................................................................................123.1.2. Analysis and characterisation of IP............................................................................123.1.3. Stability......................................................................................................................12

3.2. Investigational product.......................................................................................................123.2.1. Formulation................................................................................................................123.2.2. Manufacturer..............................................................................................................123.2.3. Final dosage form and presentation............................................................................123.2.4. Posology.....................................................................................................................133.2.5. Container and packaging............................................................................................133.2.6. Storage and handling..................................................................................................133.2.7. Stability......................................................................................................................13

3.3. Development pharmaceutics..............................................................................................134. Non-clinical studies....................................................................................................................14

4.1. Nonclinical Pharmacology.................................................................................................144.1.1. Summary....................................................................................................................144.1.2. In vitro Pharmacology................................................................................................144.1.3. In vivo Pharmacology................................................................................................14

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4.1.4. Mechanism of action..................................................................................................144.2. Pharmacokinetics and Product Metabolism in Animals.....................................................14

4.2.1. Summary....................................................................................................................144.2.2. Method of Analysis....................................................................................................144.2.3. Single-dose Absorption, Distribution, Metabolism and Excretion............................144.2.4. Multiple-dose Absorption, Distribution, Metabolism and Elimination....................154.2.5. Drug interactions........................................................................................................15

4.3. Toxicology and safety studies............................................................................................174.3.1. Summary....................................................................................................................174.3.2. Acute toxicology........................................................................................................174.3.3. Repeat dose toxicology..............................................................................................174.3.4. Toxicokinetics............................................................................................................174.3.5. Chronic toxicology.....................................................................................................174.3.6. Reproductive toxicology............................................................................................184.3.7. Safety pharmacology..................................................................................................184.3.8. Genotoxicity (Mutagenicity)......................................................................................204.3.9. Carcinogenicity..........................................................................................................204.3.10. Special studies............................................................................................................20

5. Effects in humans.......................................................................................................................215.1. Introduction........................................................................................................................215.2. Clinical Development Program..........................................................................................215.3. Pharmacokinetics, Pharmacodynamics and Product Metabolism in Humans...................215.4. Clinical experience.............................................................................................................22

5.4.1. Dose response.............................................................................................................225.4.2. Safety and Efficacy....................................................................................................225.4.3. Laboratory data and other safety parameters.............................................................225.4.4. Individual study summaries........................................................................................225.4.5. Benefit – Risk Assessment.........................................................................................22

5.5. Registration and Marketing experience..............................................................................226. Summary of data and guidance for the investigator...................................................................23

6.1. Composition.......................................................................................................................236.2. Presentation........................................................................................................................236.3. Posology and route of administration.................................................................................236.4. Storage and stability...........................................................................................................236.5. Pharmacokinetics of investigational product.....................................................................236.6. Bioanalytical evaluation.....................................................................................................236.7. Mitigation of overdose risk................................................................................................236.8. Expedited Safety Reports...................................................................................................236.9. Warnings, precautions........................................................................................................23

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6.10. Contraindications................................................................................................................236.11. Adverse events...................................................................................................................236.12. Participant populations.......................................................................................................23

6.12.1. Pregnancy and Breast-Feeding...................................................................................236.12.2. Paediatric Use.............................................................................................................236.12.3. Geriatric Use...............................................................................................................24

7. References..................................................................................................................................24

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LIST OF TABLES

Table 2-1: Safety ratios for single oral doses..................................................................................................10Table 3-1: Composition and characteristics of active ingredient.....................................................................11Table 3-2: General investigational drug product Information..........................................................................12Table 4-1: Mean plasma pharmacokinetic parameters for IP after single-dose administration.......................14Table 4-2: Summary table of Pharmacology studies......................................................................................16Table 4-3: Summary table of Toxicology studies............................................................................................19Table 5-1: Pharmacokinetic parameters of IP following single-dose administration in study no.....................21

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LIST OF FIGURES

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LIST OF ABBREVIATIONS

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1 Summary

1.1 Background

Disease aetiology and available treatments

1.2 Overview of investigational product

What is it?

What’s it do?

How’s it work?

Administered how/

Similarity to other compounds

1.3 Chemistry, Manufacturing and Controls

The IP has been manufactured in accordance with Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) for toxicological and clinical studies respectively.

The IP is produced utilising a process involving

1.4 Nonclinical Studies

1.4.1Pharmacology

There are no fully validated animal models for XXXX. No in vivo assessment of the efficacy of IP has been conducted.

1.4.2Pharmacokinetics

Pharmacokinetic studies were conducted in

1.4.3Toxicology

1.5 Clinical Experience

As of the date of this Investigator’s Brochure, the IP has not been administered to humans.

1.6 Development plan

Initial Phase I investigations in healthy volunteers will be used to assess the safety and tolerability of IP when administered weekly up to doses of XX mg/kg. Data derived from preliminary pharmacokinetic information will be used to design a subsequent Phase Ib study …..

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2 Introduction

Overview of targeted disease and indication

2.1 Investigational product

2.2 Rationale for clinical development

2.3 Dose justificationTable 2-1: Safety ratios for single oral doses

Human Single Dose Rat NOAEL XX mg/kg/day Dog NOAEL XXX mg/kg/day

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3 Physical, Chemical and Pharmaceutical Properties AND Formulation

Drug substanceThe active pharmaceutical ingredient is

API is structurally similar to (add info)

Table 3-2: Composition and characteristics of active ingredient

NAME

INTERNATIONAL NOMENCLATURE

SPONSOR NAME

CAS NUMBER

STRUCTURE

MOLECULAR FORMULA

MOLECULAR WEIGHT

DESCRIPTION

EXAMPLE: IP IS A SYNTHETIC XXXX. THE ACTIVE IS PRODUCED IN A SINGLE STEP FROM XXX WITH A PURITY TYPICALLY GREATER THAN 99%.

IP IS A WHITE TO OFF-WHITE CRYSTALLINE XXXX SALT WITH A PKA OF XX. THE MELTING POINT IS AROUND XX°C. THEACTIVE HAS A WATER SOLUBILITY OF XX MG/ML (AT PH XX).

ODOUR

SOLUBILITY

PROPERTIES

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3.1.1Manufacture

The active pharmaceutical ingredient XXX, is manufactured and purified through a series of proprietary processing steps which have been validated and performed in accordance with GLP/GMP under license at:

State name and address of manufacturer.

3.1.2Analysis and characterisation of IP

The identity of IP is confirmed by HPLC and MS with a retention time of XXmin in chromatograms etc. Purity is confirmed by XXX and analytical assay. Impurities are assessed by …

3.1.3Stability

3.2 Investigational product

3.2.1Formulation

The clinical product is formulated in combination with the ingredients shown in Table 3-2 using a series of proprietary processing steps prior to sterilisation by XXX and dispensing into XXXX. IP is formulated to contain XX% active pharmaceutical ingredient.

Table 3-3: General investigational drug product Information

INGREDIENT SPECIFICATION PURPOSE CONC (MG/ML)

ACTIVE BP/USP?? ACTIVE

EXCIPIENT EXCIPIENT

EXCIPIENT EXCIPIENT

EXCIPIENT EXCIPIENT

SOLUTE SOLVENT

3.2.2Manufacturer

3.2.3Final dosage form and presentation

The IP is supplied in a 5mL glass vial and is formulated at XX% of API and stored at RT.

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3.2.4Posology

Information on exact dose and dosing regimen is provided in the applicable approved study protocol.

3.2.5Container and packaging

5 mL glass vials are packaged in cartons of 5 …..and shipped under ambient conditions to the clinical trial site.

3.2.6Storage and handling

The vials are to be stored at RT [15°–30°C (59°–86°F)], protected from light in a secure area with limited access to appropriate pharmacists or study personnel.

3.2.7Stability

Current stability information utilising the GMP material has demonstrated that the IP is stable at RT for up to 12 months.

The stability program is currently ongoing.

3.3 Development pharmaceutics

If required

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4 Non-clinical studies

Nonclinical Pharmacology

4.1.1Summary

4.1.2In vitro Pharmacology

4.1.2.1 Individual study summaries

4.1.3In vivo Pharmacology


Animal models for XXX have not been validated for the prediction of XXXX efficacy in humans. In vivo studies to assess efficacy of XXX in XXX have not been conducted to date.

4.1.4Mechanism of action

Brief overview…

Further information regarding the mechanism of action is provided in Section XX.

4.2 Pharmacokinetics and Product Metabolism in Animals

4.2.1Summary

Nonclinical pharmacokinetic studies have characterised basic pharmacokinetic parameters in mice, rats and beagle dogs after single IV dose administration of IP.

4.2.2Method of Analysis

4.2.3Single-dose Absorption, Distribution, Metabolism and ExcretionTable 4-4: Mean plasma pharmacokinetic parameters for IP after single-dose administration

Species Ref Dose

(mg/kg)

Route AUCinf

(μg.h/mL)

Cmax

(μg/mL)

CL

(mL/kg/min)

Vss

(L/kg)

T1/2

(h)

F%

Mouse

Rat

Rabbit

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Dog

Monkey


4.2.3.2 Absorption

4.2.3.3 Distribution

4.2.3.4 Metabolism

4.2.3.5 Excretion

4.2.4Multiple-dose Absorption, Distribution, Metabolism and Elimination


4.2.5Drug interactions

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Table 4-5: Summary table of Pharmacology studies

Study number /Title GLP Species/

strain

No/sex/

group

Formulation

Dose/Regimen

Route of admin.

Duration

Results

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4.3 Toxicology and safety studies

4.3.1Summary

4.3.2Acute toxicology


4.3.3Repeat dose toxicology


Good to include table of dosing for repeated studies, group, dose, number/sex for main study, TK and PD arms.

4.3.3.2 Toxicokinetic parameters

4.3.3.3 Mortality and clinical observations

4.3.3.4 Clinical pathology and organ weights

4.3.3.5 Histopathological changes

4.3.4Toxicokinetics


4.3.5Chronic toxicology


No studies on chronic toxicology have been conducted on IP to date. Provide justification such as clinical study design.




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4.3.6Reproductive toxicology

No studies on reproductive toxicity have been conducted on IP to date. Provide justification. Repeat dose testing, discuss results of reproductive organs.


4.3.7Safety pharmacology





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Table 4-6: Summary table of Toxicology studies

Study number /Title GLP Species/

strain

No/sex/

group

Formulation

Dose/Regimen

Route of admin.

Duration

Results


Investigator’s Brochure


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4.3.8Genotoxicity (Mutagenicity)


4.3.9Carcinogenicity


No studies on carcinogenicity have been conducted on IP to date. Provide justification.

4.3.10 Special studies


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5 Effects in humans

Introduction

5.1 Clinical Development Program

The initial clinical study will be a randomised, double-blind, single dose, dose escalation study to evaluate the safety, tolerability and pharmacokinetics of IP following IV infusion in healthy male volunteers. Doses will start at 100 mg, escalating to 500 mg after evaluation of results from lower dose investigations. Doses will not exceed 500 mg.

Consideration of the data will lead to a safety, tolerability, pharmacokinetic and pharmacodynamic Phase Ib study utilising multiple ascending doses in XXX participants.

5.2 Pharmacokinetics, Pharmacodynamics and Product Metabolism in Humans

Single doses of XX mg IP in healthy participants resulted in linear and near dose-proportional increases in plasma concentrations of IP with increasing dose (mean Cmax and AUC values increased XX-fold, respectively, overall). The mean Cmax of IP ranged from XX–XX µg/mL, and the mean AUC0–inf ranged from XX-XX µg·h/mL. The mean Tmax was XX–XX hours after dosing, with a mean terminal half-life (T1/2) of XX–XX hours. IP was the major component excreted in urine at all dose levels. Approximately XX–XX% (molecular equivalent) of administered IP was recovered in urine as IP, suggesting that at least that percentage of IP is absorbed.

Table 5-7: Pharmacokinetic parameters of IP following single-dose administration in study no.

Parameter IP

200 mg (n=6) 500 mg (n=6) 1000 mg (n=6)

Cmax (μg.h/mL)

Tmax (h)

T1/2 (h)

AUC0–24 (µg·h/mL)

AUC0–inf (µg·h/mL)

CL (L/h)

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5.3 Clinical experience

5.3.1Dose response

5.3.2Safety and Efficacy

5.3.3Laboratory data and other safety parameters

5.3.4Individual study summaries

5.3.4.1 Study no.

5.3.4.2 Study no. (ongoing)

5.3.5Benefit – Risk Assessment

5.4 Registration and Marketing experience

Ta date, IP has not been registered for use or marketed in any jurisdiction.

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6 Summary of data and guidance for the investigator

Composition

6.1 Presentation

IP is presented in 10 mL vials for reconstitution prior to administration.

6.2 Posology and route of administration

6.3 Storage and stability

6.4 Pharmacokinetics of investigational product

6.5 Bioanalytical evaluation

6.6 Mitigation of overdose risk

6.7 Expedited Safety Reports

6.8 Warnings, precautions

Insufficient experience exists with IP to provide comprehensive warning guidance. The pharmacokinetics of IP is currently unknown. The investigational product will be administered at a dose of XXXmg etc. Some brief information on putative drug-drug interactions as related to dosing with similar class of compound and potential CYT inhibition criteria.

6.9 Contraindications

IP is contraindicated for use in participants with known hypersensitivity to the active substance or any of the excipients.

6.10 Adverse events

6.11 Participant populations

The investigational compound XXXXX must only be administered in accordance with the approved study protocol inclusion/exclusion criteria.

6.11.1 Pregnancy and Breast-Feeding

No studies of IP in pregnant or lactating women have been conducted. Pregnant and nursing women should not receive IP until further information becomes available. Women of childbearing potential are excluded from participating in IP clinical studies. Sexually active men must use contraception and inform their partners of the possible risks described in this document where and if applicable.

6.11.2 Paediatric Use

No studies on the use of IP in paediatric participants have been conducted.

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6.11.3 Geriatric Use

No studies on the use of IP in geriatric participants have been conducted.

References

Date: ; Version;

Documents

OHMR SOP Template - Home | Queensland Health · Web viewThis Clinical Investigator’s Brochure (CIB) was subject to critical review and has been approved by the following persons: